Diabetes mellitus is a very common disease, a cause of substantial morbidity, and a leading cause of premature death throughout the world. Evidence indicates that available treatment with insulin and diet has had little influence on the development and progression of the debilitating vascular complications that characterize the disease. Although much remains to be learned about the etiology and pathogenesis of diabetes, transplantation of the whole pancreas or islets of Langerhans represents potential means of curing the conditions that are worthy of serious investigation. Such investigation must be conducted in animal models of diabetes because of the prohibitive risks and many years of observation that studies in humans must entail. Work in our laboratory has produced a consistently successful technique of heterotopic pancreas transplantation, both with and without the duodenum, in rats. By using highly inbred rats, this experimental model has provided the opportunity to perform long-term studies of endocrine and exocrine function, morphology and effects on diabetes. Furthermore, the opportunity exists to evaluate the influence of immunosuppression regimens on pancreas allografts between rats of different strains. Studies completed thus far have demonstrated that whole pancreas transpslants consistently control the metabolic abnormalities of alloxan diabetes for the full, natural life-span of the rat. The critical question that remains in regard to all forms of pancreas replacement therapy is: Will provision of physiologic islet function by means of a whole pancreas or isolated islet transplant prevent, stabilize and reverse the renal, opthalmic, neural and vascular complications of diabetes? The answer to this question has important bearing on the therapy of diabetes, and profound implications regarding its pathogenesis. The proposed research is designed to answer this question by detailed studies of the effects of whole pancreas and isolated islet transplants on the pathologic manifestations of diabetess in the rat with alloxan diabetes, a model in which we and others have documented the development of severe nephropathy, retinopathy, neuropathy and microangiopathy similar in many respects to the lesions found in human diabetes.